An increased understanding of the intracellular mechanisms regulating colonic epithelial cell proliferation is vital because it will provide an insight into the events associated with ulcer healing and malignant transformation. In this vein, numerous investigations have shown the hormone gastrin to be trophic to most of the mucosa of the digestive tract. However, the mechanisms by which gastrin stimulate mucosal growth have not been examined. We propose to identify the signals, the mechanisms that precede, and the intracellular events that regulate colonic epithelial trophic response to gastrin. Specifically. we will investigate whether gastrin stimulates polyphosphoinositide hydrolysis with subsequent Ca2+ mobilization, activates protein kinase C enzyme system, modulates the level of intracellular cAMP, and initiates its stimulatory effect by activating a guanine nucleotide binding protein. Corollary studies will also be carried out utilizing MC-26 gastrin responsive cell line and in vivo animal model. The ultimate hope is to unravel, in molecular terms, the pathways by which hormones regulate colonic epithelial cell proliferation. Pharmacological manipulation of these events may perhaps form the basis of a rationally designed selective therapeutic agents for ulcer healing and control of malignant transformation.